Manuela Ventura1, Nicholas Bernards1, Raquel De Souza1, Inga B Fricke1, Bart S Hendriks2, Jonathan B Fitzgerald2, Helen Lee2, Stephan G Klinz2,3, Jinzi Zheng4,5. 1. TECHNA Institute for the Advancement of Technology for Health, University Health Network, Toronto, Ontario, Canada. 2. Merrimack Pharmaceuticals, Inc., Cambridge, MA, USA. 3. Ipsen Bioscience, Cambridge, MA, USA. 4. TECHNA Institute for the Advancement of Technology for Health, University Health Network, Toronto, Ontario, Canada. jinzi.zheng@rmp.uhn.on.ca. 5. Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada. jinzi.zheng@rmp.uhn.on.ca.
Abstract
PURPOSE: Hypoxia is linked to aggressiveness, resistance to therapy, and poor prognosis of pancreatic tumors. Liposomal irinotecan (nal-IRI, ONIVYDE®) has shown potential in reducing hypoxia in the HT29 colorectal cancer model, and here, we investigate its therapeutic activity and ability to modulate hypoxia in patient-derived orthotopic tumor models of pancreatic cancer. PROCEDURES: Mice were randomized into nal-IRI treated and untreated controls. Magnetic resonance imaging was used for monitoring treatment efficacy, positron emission tomography (PET) imaging with F-18-labelled fluoroazomycinarabinoside ([18F]FAZA) for tumor hypoxia quantification, and F-18-labelled fluorothymidine ([18F]FLT) for tumor cell proliferation. RESULTS: The highly hypoxic OCIP51 tumors showed significant response following nal-IRI treatment compared with the less hypoxic OCIP19 tumors. [18F]FAZA-PET detected significant hypoxia reduction in treated OCIP51 tumors, 8 days before significant changes in tumor volume. OCIP19 tumors also responded to therapy, although tumor volume control was not accompanied by any reduction in [18F]FAZA uptake. In both models, no differences were observable in [18F]FLT uptake in treated tumors compared with control mice. CONCLUSIONS: Hypoxia modulation may play a role in nal-IRI's mechanism of action. Nal-IRI demonstrated greater anti-tumor activity in the more aggressive and hypoxic tumor model. Furthermore, hypoxia imaging provided early prediction of treatment response.
PURPOSE:Hypoxia is linked to aggressiveness, resistance to therapy, and poor prognosis of pancreatic tumors. Liposomal irinotecan (nal-IRI, ONIVYDE®) has shown potential in reducing hypoxia in the HT29 colorectal cancer model, and here, we investigate its therapeutic activity and ability to modulate hypoxia in patient-derived orthotopic tumor models of pancreatic cancer. PROCEDURES: Mice were randomized into nal-IRI treated and untreated controls. Magnetic resonance imaging was used for monitoring treatment efficacy, positron emission tomography (PET) imaging with F-18-labelled fluoroazomycinarabinoside ([18F]FAZA) for tumor hypoxia quantification, and F-18-labelled fluorothymidine ([18F]FLT) for tumor cell proliferation. RESULTS: The highly hypoxic OCIP51 tumors showed significant response following nal-IRI treatment compared with the less hypoxic OCIP19 tumors. [18F]FAZA-PET detected significant hypoxia reduction in treated OCIP51 tumors, 8 days before significant changes in tumor volume. OCIP19 tumors also responded to therapy, although tumor volume control was not accompanied by any reduction in [18F]FAZA uptake. In both models, no differences were observable in [18F]FLT uptake in treated tumors compared with control mice. CONCLUSIONS:Hypoxia modulation may play a role in nal-IRI's mechanism of action. Nal-IRI demonstrated greater anti-tumor activity in the more aggressive and hypoxic tumor model. Furthermore, hypoxia imaging provided early prediction of treatment response.
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